Substitution Effect of the Trifluoromethyl Group on the Bioactivity in Medicinal Chemistry: Statistical Analysis and Energy Calculations

The substitution of methyl (Me or −CH3) by trifluoromethyl (TFM or −CF3) is frequently used in medicinal chemistry. However, the exact effect of −CH3/–CF3 substitution on bioactivity is still controversial. We compiled a data set containing 28 003 pairs of compounds with the only difference that −CH3 is substituted by −CF3, and the statistical results showed that the replacement of −CH3 with −CF3 does not improve bioactivity on average. Yet, 9.19% substitution of −CH3 by −CF3 could increase the biological activity by at least an order. A PDB survey revealed that −CF3 prefers Phe, Met, Leu, and Tyr, while −CH3 prefers Leu, Met, Cys, and Ile. If we substitute the −CH3 by −CF3 near Phe, His, and Arg, the bioactivity is most probably improved. We performed QM/MM calculations for 39 −CH3/–CF3 pairs of protein–ligand complexes and found that the −CH3/–CF3 substitution does achieve a large energy gain in some systems, although the mean energy difference is subtle, which is consistent with the statistical survey. The −CF3 substitution on the benzene ring could be particularly effective at gaining binding energy. The maximum improvements in energy achieved −4.36 kcal/mol by QM/MM calculation. Moreover, energy decompositions from MM/GBSA calculations showed that the large energy gains for the −CH3/–CF3 substitution are largely driven by the electrostatic energy or the solvation free energy. These findings may shed some light on the biological activity profile for −CH3/–CF3 substitution, which should be useful for further drug discovery and drug design.